The Journal of Neuroscience · 10 authors, 5 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
Postmortem human brain analysis and a novel transgenic mouse model were used to test whether SHANK3a loss contributes to Alzheimer's disease symptoms and neuropathology. Shank3a deficiency alone did not impair cognition, but when combined with AD neuropathology in mice, it synergistically impaired object recognition memory and increased anxiety-like behavior, while also elevating soluble Aβ42 and human tau levels.
Postmortem parietal cortex samples from individuals with AD and controls were analyzed alongside a transgenic mouse model in which hemizygous Shank3Δex4-9 mice were crossed with hemizygous 3xTg-AD mice. Human postmortem analysis revealed approximately 40% lower SHANK3a in AD parietal cortex, with levels correlating with global cognitive scores and tau accumulation. In the mouse model, neither Shank3a haploinsufficiency alone nor AD transgene expression alone produced significant object recognition deficits, but their combination impaired object recognition memory at 9, 12, and 18 months of age and precipitated anxiety-like behavior at 9 and 12 months. Shank3a deficiency also increased soluble Aβ42 in the hippocampus and cortex and elevated soluble human tau in the cortex at 18 months. Levels of other postsynaptic scaffold proteins (PSD-95, drebrin, homer1) were unchanged by Shank3a loss. Limitations include the correlational nature of human data, the use of hemizygous rather than full knockouts potentially allowing isoform compensation, and the lack of direct human intervention evidence. The findings are consistent with a synergistic role of Shank3a deficiency in AD cognitive impairment.
